Antibiotic "Dysbiosis" in Preterm Infants

Phase 2

Completed

• Conditions: Bacteremia; Chronic Lung Disease; Enterocolitis, Necrotizing; Ileal Perforation; Bronchopulmonary Dysplasia; Periventricular Leukomalacia; Intraventricular Hemorrhage
• Interventions: Drug: Antibiotic; Other: Gastric fluid; Other: Breast milk; Other: Stool samples; Drug: Antibiotics

• Registration Number: NCT02784821
• Lead Sponsor: University of Florida

Brief Summary

Prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities, including necrotizing enterocolitis (NEC), late-onset sepsis, bronchopulmonary dysplasia (BPD), and mortality.

The hypothesis is that early and prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities. It is possible that the effect of this widespread antibiotic use outweighs the potential benefits. This study will randomize preterm infants born at less than 33 weeks gestation to either pre-emptive antibiotics or no-pre-emptive antibiotics.

The purpose of this research is to evaluate the risks and benefits of current practice to determine optimal levels of antibiotic use that protects the babies from infection with minimal effect on the microbiome and subsequent adverse outcomes related to overuse of antibiotics.

Detailed Description

A majority of preterm very low birthweight (VLBW) infants are exposed to antibiotics. Surveys from large databases in the US show that the rate of culture proven bacteremia in these infants at birth is only between 1-2 percent.

Antibiotic use, especially when repeated, induces a perturbation ("dysbiosis") in gut microbiota that may not recover to the basal state. Antibiotic use increases the risk of subsequent disease and adverse outcomes. The dependence of the developing immune system on the intestinal microbiota is supported by emerging evidence from studies in animals demonstrating decreased resistance to subsequent disease with early exposure to antibiotics.

A retrospective review of 50,0261 neonates across 127 neonatal intensive care units (NICUs) from California showed a forty-fold variation in NICU antibiotic prescribing practice with similar burdens of proven infection and mortality. A large number of preterm infants are thus subjected to a potentially harmful course of antibiotics that provides no clear benefit. There remains a major gap in our understanding of antibiotic-related intestinal microbial dysbiosis and how this may result in disease.

There will be two aims. In the first aim, a prospective, randomized pilot study, will test the effects of pre-emptive postnatal antibiotics on the microbiome, metabolome and inflammatory responses in the neonate during the NICU course. The second aim will assess the effects of pre-emptive postnatal antibiotics on adverse outcomes in the neonate while in the NICU. The hypothesis is that higher antibiotic use will not be associated with decreased early onset sepsis and in fact, will be associated with increased adverse outcomes including retinopathy of prematurity, necrotizing enterocolitis, spontaneous ileal perforation, late onset sepsis, chronic lung disease, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, and mortality.

Study Timeline

• Study First Submitted: 2016-05-03
• Study First Submitted QC: 2016-05-24
• Study First Posted: 2016-05-27
• Study Start: 2017-01-16
• Primary Completion: 2019-09-11
• Study Completion: 2019-09-11
• Results First Submitted: 2021-02-08
• Status Verified: 2024-06
• Results First Submitted QC: 2024-06-03
• Last Update Submitted: 2024-06-03
• Results First Posted: 2024-06-05
• Last Update Posted: 2024-06-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 98

Inclusion Criteria

• All infants less than 33 weeks gestation.

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Exclusion Criteria

• Infants who are non-viable at birth.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A - Antibiotics Indicated	Gastric fluid	These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group B - antibiotics not indicated	Gastric fluid	These neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors. Antibiotics is not indicated for this group as standard of care. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group A - Antibiotics Indicated	Breast milk	These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group B - antibiotics not indicated	Breast milk	These neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors. Antibiotics is not indicated for this group as standard of care. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CI/randomized to antibiotics	Gastric fluid	This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group A - Antibiotics Indicated	Antibiotic	These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group A - Antibiotics Indicated	Stool samples	These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CII/randomized to no antibiotics	Breast milk	This group will be randomized not to receive standard of care antibiotics. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group B - antibiotics not indicated	Stool samples	These neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors. Antibiotics is not indicated for this group as standard of care. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CI/randomized to antibiotics	Breast milk	This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CI/randomized to antibiotics	Stool samples	This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CI/randomized to antibiotics	Antibiotics	This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CII/randomized to no antibiotics	Gastric fluid	This group will be randomized not to receive standard of care antibiotics. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Group CII/randomized to no antibiotics	Stool samples	This group will be randomized not to receive standard of care antibiotics. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.

Primary Outcome Measures

Name	Time	Method
Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death	Until discharge from the NICU, up to 1 year	Enrolled subjects' medical record will be reviewed to determine the number of patients with the composite outcome and the association between antibiotic administration and the components of the composite outcome

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Late Onset Sepsis	Until discharge from the NICU, up to 1 year	Enrolled subjects' medical record will be reviewed to determine the number of patients who developed bacteremia after the first week of life (late onset sepsis) and the association between antibiotic administration and the development of late onset sepsis.
Number of Deaths	until discharge from the NICU, up to one year.	Enrolled subjects' medical record will be reviewed to determine the number of death prior to discharge from neonatal intensive care unit
Number of Participants With Bronchopulmonary Dysplasia (BPD)	Until discharge from the NICU, up to 1 year	Enrolled subjects' medical record will be reviewed to determine the number of patients who developed BPD and the association between antibiotic administration and diagnosis of BPD.
Number of Participants With Necrotizing Enterocolitis (NEC)	Until discharge from the NICU, up to 1 year	Enrolled subjects' medical record will be reviewed to determine the number of patients who developed NEC and the association between antibiotic administration and necrotizing enterocolitis
Length of Stay.	Average days +/- standard deviation of hospitalization, up to 15 weeks	length of stay in NICU in days.

Trial Locations

Locations (1)

University of Florida; 🇺🇸 Gainesville, Florida, United States